Abstract 4579: A three-dimensional model of glioblastoma for discovery of novel therapeutics
Authors: Viktoriia Kriuchkovskaia, Brendan A. Harley, Rebecca B. Riggins
Journal: Cancer Research (2023)

Abstract Statement of Purpose: Glioblastoma (GBM) is the most common and lethal form of brain cancer. Despite an aggressive treatment strategy, including surgical resection followed by radio- and chemotherapy, GBM has one of the highest mortality rates among all human tumors. The leading causes of this devastating prognosis are rapid recurrence and therapeutic resistance; current chemo- and immunotherapies fail to control tumor growth and progression. Temozolomide (TMZ) remains the gold standard for GBM treatment since its FDA approval for GBM in 2005. Subsequently, GBM treatment strategy has seen no significant advancement, despite TMZ providing only minimal benefit to most patients. Recent efforts to develop novel therapies for GBM have primarily involved in vivo animal models and conventional 2D cell cultures. However, animal models do not allow for elucidating specific interactions between cancer cells and tumor microenvironment (TME), while 2D models fail to depict the complex tumor architecture. In vitro biomaterial models offer an opportunity to evaluate aspects of cell-cell and cell-matrix driven responses within the complex TME. Here, we construct and validate a 3D hydrogel platform to evaluate drug response in GBM and to examine the role of TME in drug response, resistance, and local invasion. Results: Our model departs from most biomaterial platforms by assessing a wide range of TMZ concentrations and further validating drug response at low doses. Moreover, we use a set of GBM cell lines with defined shifts in TMZ response. These lines are an ideal candidate to model TMZ response &amp; resistance—a unique set of isogenically matched GBM cells (8MGBA vs. 8MGBA-TMZres; 42MGBA vs. 42MBGA-TMZres). This set exhibits TMZ responsiveness or resistance along with disparate proliferative and invasive patterns. Here, we analyze these cell models in GelMA hydrogels to elucidate mechanisms underlying the acquired TMZ resistance in GBM tumors. We validate our platform by using physiologically relevant TMZ doses, showing the possibility to study TMZ response in 3D at low, physiologically relevant (&amp;lt; 100 μM) concentrations. We determine the growth-rate (GR) inhibition, GR50, IC50, and metabolic activity to benchmark detection limits for acquired TMZ resistance in the engineered GelMA GBM model. Subsequently, we use WT and TMZres variants of 42MGBA and 8MGBA lines to determine the upper and lower bounds of detectable TMZ response in 3D GelMA hydrogels. These quantified shifts in TMZ-induced GR inhibition are a key benchmark for studies of the efficacy of novel therapeutics in patient-derived GBM models. Furthermore, we assess the effect of acquired drug resistance on local invasion of GBM. Ongoing experiments aim to adapt our platform for phenotypic drug screening and target validation of novel small-molecule therapeutics. Citation Format: Viktoriia Kriuchkovskaia, Brendan A. Harley, Rebecca B. Riggins. A three-dimensional model of glioblastoma for discovery of novel therapeutics. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4579.